Pharmaceutical antiretroviral composition

ABSTRACT

A pharmaceutical composition comprises at least one integrase inhibitor or its salt, solvate, complex, hydrate, isomer, ester, tautomer, anhydrate, enantiomer, polymorph or prodrug and at least one antiretroviral or anti-HIV agent or its salt, solvate, complex, hydrate, isomer, ester, tautomer, anhydrate, enantiomer, polymorph or prodrug.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of and claims priority to U.S. patentapplication Ser. No. 14/429,651 filed Mar. 19, 2015, published as U.S.Patent Publication US 2015-01231079 A1, which is a filing under 35U.S.C. 371 of International Application No. PCT/GB2013/000453 filed Oct.23, 2013, entitled “Pharmaceutical Antiretroviral Composition,” whichclaims priority to Indian Patent Application No. 3093/MUM/2012 filedOct. 23, 2012, which applications are incorporated by reference hereinin their entirety.

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprisinganti-retroviral agents, the manufacturing process thereof and use of thesaid composition for the prevention, treatment or prophylaxis ofretroviral diseases in the patients in need thereof.

BACKGROUND AND PRIOR ART

The human immunodeficiency virus (“HIV”) is the causative agent foracquired immunodeficiency syndrome (“AIDS”), a disease characterized bythe destruction of the immune system, particularly of CD4 T-cells withsusceptibility to opportunistic infections. In nearly all cases whereindividuals receive no treatment for HIV infection, the proliferation ofthe virus gives rise to AIDS. As of early 1999, an estimated 33.4million people are infected with HIV worldwide. Furthermore, in 2009approximately 50,000 people were newly infected with HIV in the UnitedStates [Prejean J, Song R, Hernandez A, et al. Estimated HIV incidencein the United States, 2006-2009. PLoS ONE 2011; 6(8): e7502]. It hasalso been observed that the annual rate of new infection with HIV in theentire human population has not declined. Despite this fact, the rate ofdeath due to AIDS has begun to drop in some nations primarily throughthe recent use of combination drug therapies against HIV infection.

The means by which such therapies counter HIV infection is bestunderstood with reference to the biological mechanisms of the HIV lifecycle. HIV is a member of a class of infectious agents known asretroviruses. The infectious form of HIV, a virion, is a particle thatconsists of a viral genome composed of RNA that is surrounded byproteins encoded by the genome. Infection occurs when an HIV virionenters a susceptible host cell, such as a T lymphocyte within thebloodstream. At this point, one of the viral proteins that comprise thevirion, reverse transcriptase (RT), synthesizes a double-stranded DNAcopy of the HIV RNA genome. The resulting HIV DNA enters the cellnucleus as part of a stable complex with other virion proteins. Thiscomplex contains all the necessary molecular apparatus for integrationwherein the HIV DNA is covalently inserted into the host cell's genomicDNA which is absolutely required for prolific HIV infection. It is onlyafter integration that the HIV DNA can serve as the template for theproduction of HIV proteins and RNA that will comprise progeny virions.Among these viral proteins is the HIV protease, the activity of which isnecessary for proper formation of new virions. This process, from viralentry to new virion production, is termed viral replication. Uponrelease from an infected host cell, the newly produced virions arecapable of further infecting uninfected host cells. It is throughsuccessive rounds of HIV replication and productive host cell infectionthat HIV disease spreads throughout numerous host cells and ultimatelyprogresses to AIDS.

The current strategy recommended for the treatment of HIV infection isHighly Active Antiretroviral Therapy (HAART). HAART normally consists ofa combination of antiretroviral drugs (ARV) taken together. Thesetherapies consist of simultaneous or separate administration ofcombination of drugs, which potently and selectively target differentelements of the HIV life cycle to disrupt or forestall productive HIVinfection and progression to AIDS.

For example WO2008043829 discloses a method of treating HIV whereinemtricitabine, tenofovir and nevirapine are administered once a day.

WO04087169 discloses a composition useful for the treatment orprophylaxis of viral infections comprising nevirapine and at least oneantiviral active compound such as alovudine.

US20100183716 discloses compressed tablets containing atazanavirsulfate, optionally with another active agents, e.g., anti-HIV agents,granules that contain atazanavir sulfate and an intragranular lubricantthat can be used to make the tablets, compositions comprising aplurality of the granules, processes for making the granules andtablets, and methods of treating HIV.

WO2011127244 discloses compressed tablets containing atazanavir sulfateand an acidifying agent, optionally with another active agent, e.g.,anti-HIV agents.

U.S. Pat. No. 7,432,294 disclose composition comprising one or moresolubilized HIV protease inhibiting compounds with other HIV proteaseinhibiting compound.

EP1083932 discloses homogeneous combination of abacavir, lamivudine, andzidovudine in an amount which achieves antiviral efficacy.

Although the use of combination drug therapies against HIV has proven tobe effective in many patients, the current drug regimens are far fromideal. Treatment failure often (though not always) occurs because apatient's strain of HIV may develop resistance to one or more ofantiretroviral medications. The manner by which HIV develops resistanceto antiretroviral drugs is similar to the way in which bacteria ormycobacterium develops resistance to antibiotics: for example electionof insufficiently potent drug therapy for mutant strains that areresistant to the medications administered to the patient. These mutantstrains then replace the wild-type strain due to their selectivereplication advantage in the face of drug pressure, leading to treatmentfailure.

Further the success of HAART depends on patient related factors as well,the most important being adherence. The HIV therapy is a life-longtherapy coupled with high levels of adherence to the same. This israther a demanding task for HIV infected patients due to various reasonssuch as low morale, social stigma, low immunity attributed to thedisease. Some studies have also shown that adherence to prescribed drugsover long treatment periods is generally poor. (Jintanat A. et al. SwissHIV Cohort Study. Failures of 1 week on, 1 week off antiretroviraltherapies in a randomized trial AIDS, 2003; 17:F33-F37).

Hence, such non-adherence may lead to rebound in viral replication and,in presence of sub-optimal drug concentration may lead to rapiddevelopment of drug resistance. This development of drug resistance maybe disastrous because of the complexity and cost associated with secondline regimens and the potential for transmission of drug resistant virusin the community.

The therapy may involve use of different drug combinations, which aredifficult to adhere, because of the different dosage forms foradministering each such antiretroviral drug separately. This is ofparticular importance in the case of elderly patients.

Further for most of the therapeutic agents to produce systemic effects,the oral route still represents the preferred way of administration,owing to its several advantages and high patient compliance as comparedto any other route of administration. Tablets and hard gelatin capsulesstill constitute a major portion of drug delivery systems that arecurrently available.

However, many patient groups such as the elderly, children, and patientswho are mentally retarded, uncooperative, nauseated, or on reducedliquid-intake/diets have difficulties swallowing the dosage forms suchas tablets and hard gelatin capsules. Further, those who are travelingor have little access to water are similarly affected.

Also, the route of drug administration, appearance, color, taste, tabletsize and dosing regimen are most important parameters that governpatient compliance.

Especially, the geriatric and paediatric patients experience difficultyin swallowing larger sized tablets wherein large size tablet may resultin esophageal damage due to its physical characteristics if it is notswallowed properly, which ultimately leads to poor patient compliance.

Also, oral administration of bitter drugs with an acceptable degree ofpalatability is a key issue for health care providers, especially forpaediatric patients.

Further, there has been an enhanced demand for dosage forms that aremore patient-friendly and patient compliant. Since the development costof a new drug molecule is very high, efforts are now being made to focuson the development of new drug dosage forms for existing drugs withimproved safety and efficacy together with reduced dosing frequency aswell as which are cost-effective.

Although different treatment methods and dosage regimens have beenframed in order to increase the patient adherence for treatment of HIV,there still remains a critical need for developing improved dosage formssuch as a kit composition or dosage form by which a patient isencouraged to adhere to his daily dosage regimen. The combination ofantiretroviral drugs administered in a single unit dosage form mayresult in increased patient compliance as the pill burden is reduced anddosing schedules are simplified. However, not all compounds are suitablefor administration in combinations as there are several factors thatinfluence the feasibility of combinations such as the chemicalinstability of the compounds, size of the dosage unit, potential forantagonistic or merely additive activities of the combined compounds,and difficulties in achieving a suitable formulation.

Thus there is an unmet need to find therapeutic agents suitable for usein combination to provide suitable pharmaceutical compositions to treatHIV infection and simultaneously increase the patient compliance.

OBJECT OF THE INVENTION

The object of the present invention is to provide a pharmaceuticalcomposition which is a combination therapy to treat retroviral diseases,such as HIV.

Another object of the present invention is to provide a suitablepharmaceutical antiretroviral composition which would not only beconvenient for patient administration but would also maintain patientadherence to the therapy.

Yet another object of the present invention is to provide a process ofmanufacturing such a pharmaceutical composition.

Another object of the present invention is to provide a method ofprevention, treatment or prophylaxis of diseases caused by retroviruses,especially acquired immune deficiency syndrome or an HIV infection.

Yet another object of the present invention is to provide use of thepharmaceutical composition for the treatment or prophylaxis of diseasescaused by retroviruses, especially acquired immune deficiency syndromeor an HIV infection.

SUMMARY OF THE INVENTION

According to one aspect of the present invention there is provided apharmaceutical composition comprising at least one integrase inhibitorand at least one antiretroviral or anti-HIV agent and optionally one ormore pharmaceutically acceptable excipients.

According to another aspect of the present invention there is provided aprocess for preparing the pharmaceutical composition wherein the processcomprises admixing the at least one integrase inhibitor, the at leastone antiretroviral or anti-HIV agent and optionally one or morepharmaceutically acceptable excipients.

According to a further aspect of the present invention, there isprovided the pharmaceutical composition for use in medicine.

According to a further aspect of the present invention, there isprovided the pharmaceutical composition for use in the prevention,treatment or prophylaxis of diseases caused by retroviruses, preferablyacquired immune deficiency syndrome or an HIV infection.

According to another aspect of the present invention, there is providedthe use of the pharmaceutical composition in the manufacture of amedicament for the prevention, treatment or prophylaxis of diseasescaused by retroviruses, preferably acquired immune deficiency syndromeor an HIV infection.

According to another aspect of the present invention, there is provideda method of preventing or treating diseases caused by retroviruses,preferably acquired immune deficiency syndrome or an HIV infection,wherein the method comprises administering the pharmaceuticalcomposition of the present invention to a subject in need thereof.

DETAILED DESCRIPTION

As discussed above, there is a need to develop and formulate a suitablepharmaceutical composition which would not only be convenient forpatient administration but would also maintain patient adherence to thetherapy. The inventors of the present invention have now surprisinglyfound combinations of integrase inhibitors with antiretroviral agents oranti-HIV agents for the treatment, prevention and prophylaxis ofretroviral diseases.

The present invention thus provides a pharmaceutical compositioncomprising at least one integrase inhibitor and at least one anti-HIV oranti-retroviral agent optionally with pharmaceutically acceptableexcipients.

Integrase inhibitors are a class of antiretroviral drug designed toblock the action of integrase, a viral enzyme that inserts the viralgenome into the DNA of the host cell. Since integration is a vital stepin retroviral replication, blocking it can halt further spread of thevirus.

The present invention thus provides a pharmaceutical compositioncomprising at least one integrase inhibitor and at least oneantiretroviral agent or anti-HIV agent, optionally with at least onepharmaceutically acceptable excipients.

It will be appreciated that the respective therapeutic agents may beadministered simultaneously or separately either in the same ordifferent pharmaceutical compositions. If there is separateadministration, it will also be appreciated that the subsequentlyadministered therapeutic agents should be administered to a patientwithin a time scale so as to achieve, or more particularly optimize,synergistic therapeutic effect of such a combined preparation.

The term “pharmaceutical composition” includes tablets, capsules (filledwith powders, pellets, beads, mini-tablets, pills, micro-pellets, smalltablet units, MUPS, disintegrating tablets, dispersible tablets,granules, and microspheres, multiparticulates), sachets (filled withpowders, pellets, beads, mini-tablets, pills, micro-pellets, smalltablet units, MUPS, disintegrating tablets, dispersible tablets,granules, and microspheres, multiparticulates) and sprinkles, however,other dosage forms such as controlled release formulations, lyophilizedformulations, modified release formulations, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, dual release formulations and the like; liquid dosage form(liquids, suspensions, solutions, emulsions, microemulsions, sprays,spot-on), injection preparations, nano formulation etc. may also beenvisaged under the ambit of the invention. Suitable excipients may beused for formulating the various dosage forms according to the presentinvention.

The term “integrase inhibitor(s)” (for example dolutegravir,elvitegravir or raltegravir) or “anti-HIV agent(s)” and “antiretroviralagent(s)” (for example nucleoside and nucleotide reverse transcriptioninhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors(NNRTIs), protease inhibitors (PIs), and maturation inhibitors (MIs))used throughout the description and claims are used in a broad sense toinclude not only the active ingredient per se but also pharmaceuticallyacceptable derivatives thereof. Suitable derivatives includepharmaceutically acceptable salts, pharmaceutically acceptable solvates,pharmaceutically acceptable hydrates, pharmaceutically acceptableisomers, pharmaceutically acceptable esters, pharmaceutically acceptableanhydrates, pharmaceutically acceptable enantiomers, pharmaceuticallyacceptable polymorphs, pharmaceutically acceptable prodrugs,pharmaceutically acceptable tautomers and/or pharmaceutically acceptablecomplexes thereof and combinations thereof.

Examples of suitable integrase inhibitors include but are not limited todolutegravir, raltegravir, MK-2048, JTK-656, elvitegravir.

Preferably, the integrase inhibitor is dolutegravir, raltegravir orelvitegravir.

The dose of dolutegravir is in the range of 1 to 50 mg, preferably inthe range of 25 to 50 mg.

The dose of raltegravir is in the range of 25 to 500 mg. For example,25, 100, 400, 500 mg. The preferred form of raltegravir is raltegravirpotassium.

The dose of elvitegravir is in the range of 1 to 200 mg, preferably inthe range of 25 to 180 mg.

Antiretroviral drugs/agents or the anti-HIV agents for the purpose ofthe present invention may be selected from nucleoside and nucleotidereverse transcription inhibitors (NRTIs), non-nucleoside reversetranscriptase inhibitors (NNRTIs), protease inhibitors (PIs), andmaturation inhibitors (MIs) and any combination thereof.

The term “nucleoside and nucleotide reverse transcriptase inhibitors”(NRTIs) as used herein means nucleosides and nucleotides and analoguesthereof that inhibit the activity of HIV-1 reverse transcriptase, theenzyme which catalyzes the conversion of viral genomic HIV-1 RNA intoproviral HIV-1 DNA.

Suitable nucleoside reverse transcriptase inhibitors (NRTIs) that may beemployed in the pharmaceutical composition of the present invention maycomprise zidovudine; didanosine; stavudine; lamivudine; abacavir;adefovir; lobucavir; entecavir; apricitabine; emtricitabine;zalcitabine; dexelvucitabine; alovudine; amdoxovir; elvucitabine;AVX754; BCH-189; phosphazid; racivir; SP1093V; stampidine; BCH-10652,β-L-FD4 (also called β-L-D4C and namedβ-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD, the purine nucleoside,(−)-β-D-2,6-diamino-purine dioxolane; and lodenosine (FddA),9(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine and anycombination thereof.

Suitable nucleotide reverse transcriptase inhibitors (NtRTIs) that maybe employed in the pharmaceutical composition of the present inventionmay comprise tenofovir and adefovir.

Preferably, the NRTIs/NtRTIs are selected from tenofovir, emtricitabine,lamivudine or zidovudine, or any combination thereof.

Suitable non-nucleotide reverse transcriptase inhibitors (NNRTIs) thatmay be employed in the pharmaceutical composition of the presentinvention may comprise nevirapine, rilpivirine, delaviridine, efavirenz,etravirine. Other NNRTIs include PNU-142721, afuropyridine-thiopyrimide; capravirine (S-1153 or AG-1 549;5-(3,5-dichlorophenyl)-thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethylcarbonate); emivirine [MKC-442;(1-(ethoxy-methyl)-5-(1-methyethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimid-inedione)];(+)-calanolide A (NSC-67545 1) and B, coumarin derivatives; DAPY(TMC120;4-{4-[4-((E)-2-cyano-vinyl)-2,6-dimethyl-phenylamino]-pyrimidin-2-ylamino-}-benzonitrile);BILR-355 BS(12-ethyl-8-[2-(1-hydroxy-quinolin-4-yloxy)-ethyl]-5-methyl-11,12-dihydro-5H-1,5,10,12-tetraaza-dibenzo[a,e]cycloocten-6-one;PHI-236(7-bromo-3-[2,5-dimethoxy-phenyl)-ethyl]-3,4-dihydro-1H-pyrido[1,2-a][-1,3,5]triazine-2-thione)and PHI-443 (TMC-278,1-(5-bromo-pyridin-2-yl)-3-(2-thiophen-2-yl-ethyl)-thiourea).

Suitable protease inhibitors (PIs) that may be employed in thepharmaceutical composition of the present invention may comprisesaquinavir; ritonavir; nelfinavir; amprenavir; lopinavir, indinavir;nelfinavir; atazanavir; lasinavir; palinavir; tipranavir; fosamprenavir;darunavir; TMC114; DMP450, a cyclic urea; BMS-2322623, BMS-232623;GS3333; KNI-413; KNI-272; LG-71350; CGP-61755; PD 173606; PD 177298; PD178390; PD 178392; U-140690; ABT-378; and AG-1549 an imidazolecarbamate. Additional PIs include N-cycloalkylglycines,α-hydroxyarylbutanamides; α-hydroxy-γ-[[(carbocyclic- orheterocyclic-substituted)amino)carbonyl]alkanamide derivatives;γ-hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides;dihydropyrone derivatives and α- and β-amino acidhydroxyethylaminosulfonamides; and N-aminoacid substituted L-lysinederivatives.

The antiretroviral agents according to the present invention may be usedin the form of salts or esters derived from inorganic or organic acids.These salts include but are not limited to acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, cyclopentanepropionate,dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate),lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate,p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containinggroups can be quaternized with such agents as loweralkyl halides, suchas methyl, ethyl, propyl, and butyl chloride, bromides, and iodides;dialkylsulfates like dimethyl, diethyl, dibutyl, and diamylsulfates,long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl bromides, and the like.

Preferably, the pharmaceutical composition comprises dolutegravir,tenofovir and emtricitabine/lamivudine optionally with one or morepharmaceutically acceptable excipients.

Alternatively, the pharmaceutical composition comprises elvitegravir,tenofovir and lamivudine optionally with one or more pharmaceuticallyacceptable excipients.

Alternatively, the pharmaceutical composition comprises elvitegravir,tenofovir and emtricitabine optionally with one or more pharmaceuticallyacceptable excipients.

Alternatively, the pharmaceutical composition comprises raltegravir,tenofovir and emtricitabine/lamivudine optionally with one or morepharmaceutically acceptable excipients.

Alternatively, the pharmaceutical composition comprises dolutegravir,lamivudine and zidovudine optionally with one or more pharmaceuticallyacceptable excipients.

Alternatively, the pharmaceutical composition comprises elvitegravir,lamivudine and zidovudine optionally with one or more pharmaceuticallyacceptable excipients.

Alternatively, the pharmaceutical composition comprises raltegravir,lamivudine and zidovudine optionally with one or more pharmaceuticallyacceptable excipients.

Alternatively, the pharmaceutical composition comprises dolutegravir,emtricitabine and lamivudine/zidovudine optionally with one or morepharmaceutically acceptable excipients.

Alternatively, the pharmaceutical composition comprises dolutegravir,tenofovir and zidovudine optionally with one or more pharmaceuticallyacceptable excipients.

Alternatively, the pharmaceutical composition comprises raltegravir,emtricitabine and lamivudine/zidovudine optionally with one or morepharmaceutically acceptable excipients.

Alternatively, the pharmaceutical composition comprises raltegravir,tenofovir and zidovudine optionally with one or more pharmaceuticallyacceptable excipients.

Alternatively, the pharmaceutical composition comprises dolutegravir,abacavir and lamivudine optionally with one or more pharmaceuticallyacceptable excipients.

Alternatively, the pharmaceutical composition comprises raltegravir,abacavir and lamivudine optionally with one or more pharmaceuticallyacceptable excipients.

Alternatively, the pharmaceutical composition comprises dolutegravir,abacavir and emtricitabine optionally with one or more pharmaceuticallyacceptable excipients.

Alternatively, the pharmaceutical composition comprises raltegravir,abacavir and emtricitabine optionally with one or more pharmaceuticallyacceptable excipients.

Suitably, the pharmaceutical composition according to the presentinvention are presented in solid dosage form suitable for oral or buccaladministration, however, other dosage forms such as liquid dosage formmay be envisaged under the ambit of the invention.

The pharmaceutical composition according to the present invention may beadministered orally through unit dosage forms including tablets,capsules (filled with powders, pellets, beads, mini-tablets, pills,micro-pellets, small tablet units, MUPS, disintegrating tablets,dispersible tablets, granules, and microspheres, multiparticulates),sachets (filled with powders, pellets, beads, mini-tablets, pills,micro-pellets, small tablet units, MUPS, disintegrating tablets,dispersible tablets, granules, and microspheres, multiparticulates) andsprinkles, however, other dosage forms such as controlled releaseformulations, lyophilized formulations, modified release formulations,delayed release formulations, extended release formulations, pulsatilerelease formulations, dual release formulations and the like; liquiddosage form (liquids, suspensions, solutions, emulsions, microemulsions,sprays, spot-on), injection preparations, nano formulation, selfemulsifying drug delivery formulations etc. may also be envisaged underthe ambit of the invention.

Suitably, the pharmaceutical antiretroviral composition according to thepresent invention may also be presented in the form of a kit comprisingat least one integrase inhibitor and at least one antiretroviral oranti-HIV agent and provides the patient with his daily regimen of drugsin a single package. This further facilitates the patient in getting thedrug regimen of the entire day in a single package which also enablesthe patient to avoid carrying of numerous medications and also confirmif the same are administered. The kit composition has an advantage overthe other packaged dosage forms in that the patient always has access tothe set of instructions for administration contained in the kit. Theinclusion of a set of instructions for administration has been shown toimprove patient compliance.

Preferably, the present invention provides a pharmaceuticalantiretroviral composition comprising dolutegravir, tenofovir,emtricitabine/lamivudine and zidovudine in a kit form.

Alternatively, the present invention provides a pharmaceuticalantiretroviral composition comprising raltegravir, tenofovir,emtricitabine/lamivudine and zidovudine in a kit form.

Alternatively, the pharmaceutical antiretroviral composition in a kitform may comprise a separate unit dosage form ofdolutegravir/raltegravir, a separate unit dosage form of tenofovir,separate unit dosage form of emtricitabine/lamivudine and separate unitdosage form of zidovudine.

The mini-tablets or granules filled in hard gelatin capsules or sachetscan be directly administered or can be administered by sprinkling themini-tablet or granules on regular meals. Alternatively, themini-tablets or granules filled in hard gelatin capsules or sachets maybe administered with liquid or semi-solid beverages such as but notlimited to, juices, water.

The mini-tablets or granules according to the present invention may alsooptionally be coated. Preferably, mini-tablets or granules according tothe present invention may be film coated. More preferably, themini-tablets or granules may be seal coated and then film coated andfurther filled in hard gelatin capsules or sachets.

A tablet formulation is the preferred solid dosage form due to itsgreater stability, less risk of chemical interaction between differentmedicaments, smaller bulk, accurate dosage, and ease of production.

Solid unit dosage forms are preferably in the form of tablets eithersingle or bilayered or multilayered tablets but other conventionaldosages such as powders, pellets, capsules and sachets may fall withinthe scope of this invention.

The pharmaceutical antiretroviral composition may be administeredsimultaneously, separately or sequentially in a single unit dosage form.

The pharmaceutical antiretroviral composition may be administered as asingle layered or bilayered or multilayered tablet wherein each layermay or may not contain drug/drugs along with pharmaceutically acceptableexcipients which are then compressed to provide either a single layered,bilayered or multilayered tablet.

Suitable excipients may be used for formulating the various dosageforms.

The term excipient used herein includes one or more of pharmaceuticallyacceptable ingredients but are not limited to carriers, diluents orfillers, binders, lubricants, glidants and disintegrants.

Non-limiting examples of suitable pharmaceutically acceptable carriers,diluents or fillers for use in the pharmaceutical composition includelactose (for example, spray-dried lactose, α-lactose, β-lactose) lactoseavailable under the trade mark Tablettose, various grades of lactoseavailable under the trade mark Pharmatose or other commerciallyavailable forms of lactose, lactitol, saccharose, sorbitol, mannitol,dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium,microcrystalline cellulose (for example, microcrystalline celluloseavailable under the trade mark Avicel), hydroxypropylcellulose,L-hydroxypropylcellulose (low substituted), hydroxypropylmethylcellulose (HPMC), methylcellulose polymers (such as, for example,Methocel A, Methocel A4C, Methocel A15C, Methocel A4M),hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene,carboxymethyl hydroxyethylcellulose and other cellulose derivatives,pre-gelatinized starch, starches or modified starches (including potatostarch, corn starch, maize starch and rice starch) and the like.

Typically glidants and lubricants may also be included in thepharmaceutical composition. Non-limiting examples include stearic acidand pharmaceutically acceptable salts or esters thereof (for example,magnesium stearate, calcium stearate, sodium stearyl fumarate or othermetallic stearate), talc, waxes (for example, microcrystalline waxes)and glycerides, light mineral oil, PEG, silica acid or a derivative orsalt thereof (for example, silicates, silicon dioxide, colloidal silicondioxide and polymers thereof, crospovidone, magnesium aluminosilicateand/or magnesium alumina metasilicate), sucrose ester of fatty acids,hydrogenated vegetable oils (for example, hydrogenated castor oil), ormixtures thereof or any other suitable lubricant.

Suitably one or more binders may also be present in the pharmaceuticalcomposition and non-limiting examples of suitable binders are, forexample, polyvinyl pyrrolidone (also known as povidone), polyethyleneglycol(s), acacia, alginic acid, agar, calcium carragenan, cellulosederivatives such as ethyl cellulose, methyl cellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose, sodiumcarboxymethylcellulose, dextrin, gelatin, gum arabic, guar gum,tragacanth, sodium alginate, or mixtures thereof or any other suitablebinder.

Suitable disintegrants may also be present in the pharmaceuticalcomposition.

Examples include, but are not limited to, hydroxylpropyl cellulose(HPC), low density HPC, carboxymethylcellulose (CMC), sodium CMC,calcium CMC, croscarmellose sodium; starches exemplified under examplesof fillers and also carboxymethyl starch, hydroxylpropyl starch,modified starch; crystalline cellulose, sodium starch glycolate; alginicacid or a salt thereof, such as sodium alginate or their equivalents andany combination thereof.

There is also provided a hot melt extruded pharmaceutical compositioncomprising antiretroviral drug(s), for example at least one integraseinhibitor and at least one antiretroviral agent or anti-HIV agent asdescribed previously, and at least one water soluble and/or waterswellable and/or water insoluble polymer or combination thereof andoptionally one or more pharmaceutically acceptable excipients.

Water soluble polymers which may be used in the pharmaceuticalcomposition of the present invention, include, but are not limited to,homopolymers and co-polymers of N-vinyl lactams, especially homopolymersand co-polymers of N-vinyl pyrrolidone e.g. polyvinylpyrrolidone (PVP),co-polymers of PVP and vinyl acetate, co-polymers of N-vinyl pyrrolidoneand vinyl acetate (Copovidone) or vinyl propionate, dextrins such asgrades of maltodextrin, cellulose esters and cellulose ethers, highmolecular polyalkylene oxides such as polyethylene oxide andpolypropylene oxide and co-polymers of ethylene oxide, propylene oxideand mixtures thereof.

Water insoluble polymers which may be used in the pharmaceuticalcomposition of the present invention, include, but are not limited to,acrylic copolymers e.g. Eudragit E100 or Eudragit EPO; Eudragit L30D-55,Eudragit FS30D, Eudragit RL30D, Eudragit RS30D, Eudragit NE30D,Acryl-Eze; polyvinylacetate, for example, Kollicoat SR 30D; cellulosederivatives such as ethylcellulose, cellulose acetate e.g. Surelease,Aquacoat ECD and Aquacoat CPD and mixtures thereof.

Water swellable polymers that may be used in the pharmaceuticalcomposition of the present invention include but are not limited topolyethylene oxide; poly (hydroxy alkyl methacrylate); poly (vinyl)alcohol, having a low acetal residue, which is cross-linked withglyoxal, formaldehyde or glutaraldehyde and having a degree ofpolymerization of from 200 to 30,000; a mixture of methyl cellulose,cross-linked agar and carboxymethyl cellulose; Carbopol® carbomer whichis an acidic carboxy polymer; Cyanamer® polyacrylamides; cross-linkedwater swellable indene-maleic anhydride polymers; Goodrich® polyacrylicacid; starch graft copolymers; Aqua Keeps® acrylate polymerpolysaccharides composed of condensed glucose units such as diestercross-linked polyglucan, and the like; Amberlite® ion exchange resins;Explotab® sodium starch glycolate; Ac-Di-Sol® croscarmellose sodium ormixtures thereof.

The one or more optional pharmaceutically acceptable excipients mayinclude a plasticizer.

Plasticizers reduce the viscosity of the polymer melt and thereby allowfor lower processing temperature and extruder torque during hot meltextrusion. They further decrease the glass transition temperature of thepolymer.

Plasticizers which may be used in the pharmaceutical composition of thepresent invention, include, but are not limited to, polysorbates such assorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitanmonostearate, sorbitan monoisostearate; citrate ester type plasticizerslike triethyl citrate, citrate phthalate; propylene glycol; glycerin;polyethylene glycol (low & high molecular weight); triacetin;dibutylsebacate, tributylsebacate; dibutyltartrate, dibutyl phthalate,glycerol palmitosterate and mixtures thereof.

The pharmaceutical composition may be prepared by admixing at least oneintegrase inhibitor, at least one antiretroviral or anti HIV agentaccording to the present invention with other suitable pharmaceuticallyacceptable excipients such as sweeteners, vehicle/wetting agents,buffering agents, coloring agents, flavoring agents, preservatives,viscosity enhancing/thickening agents and the like or combinationsthereof.

The pharmaceutical composition of the present invention may be preparedby admixing the at least one integrase inhibitor, the at least oneantiretroviral or anti-HIV agent either separately or in combination,optionally, with one or more pharmaceutically acceptable excipients.This blend may be subjected to granulation or directly compacted toobtain granules.

The pharmaceutical composition according to the present invention may beprepared through various techniques or processes known in the art whichincludes, but are not limited to direct compression, wet granulation,roll compaction, dry granulation, melt granulation, melt extrusion,spray drying, solution evaporation or combinations thereof.

It may be acknowledged by a person skilled in the art that the abovementioned techniques may either be used alone or in combination thereof.

The pharmaceutical composition of the present invention can be processedby roll compaction.

The process comprises sifting and dry mixing the at least one integraseinhibitor, the at least one antiretroviral agent or anti-HIV agent andoptionally with one or more excipients followed by compaction and sizingto obtain granules.

The process further comprises lubricating the granules and eithercompressing the lubricated granules to form a single layered tablet,bi/multi layered tablet or a mini-tablet; or filling the lubricatedgranules into hard gelatin capsules or sachets.

The pharmaceutical composition according to the present invention mayalso optionally be coated, i.e. seal coated or film coated. Preferably,the pharmaceutical composition may be seal coated and then film coated.

The pharmaceutical composition may be film coated with, but not limitedto, Ready colour mix systems (such as Opadry™ colour mix systems) andpolyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol.

The pharmaceutical antiretroviral composition may be seal coatedfollowed by film coating using polymeric materials, such as but notlimited to hydroxypropylmethylcellulose (HPMC 6 CPS, or HPMC 6 CPS toHPMC 15CPS grade), hydroxypropylcellulose, polyvinylpyrrolidone,methylcellulose, carboxymethylcellulose, hypromellose, acacia, gelatin,and polyvinyl alcohol-polyethylene glycol copolymer and polyvinylalcohol and the like or combinations thereof.

The pharmaceutical composition of the present invention may beformulated for paediatric patients and from the point of view ofpaediatric patient acceptability suitable bulking agents may beincorporated, in the pharmaceutical antiretroviral compositioncomprising saccharides, including monosaccharides, disaccharides,polysaccharides and sugar alcohols but not limited to arabinose,lactose, dextrose, sucrose, fructose, maltose, mannitol, erythritol,sorbitol, xylitol, lactitol, powdered cellulose, microcrystallinecellulose, purified sugar and their derivatives and the like orcombinations thereof.

Accordingly, the pharmaceutical composition of the present invention mayfurther incorporate suitable pharmaceutically acceptable flavourants,such as, but not limited to, citric acid, tartaric acid, lactic acid,orange permaseal, strawberry cream flavour or other natural flavourantsand sweeteners such as, but not limited to, aspartame and the like orcombinations thereof.

The pharmaceutical composition according to the present invention mayfurther incorporate suitable pharmaceutically acceptable colourants,such as, but not limited to, red oxide of iron and ferric oxide yellow.

The pharmaceutical composition according to the present invention mayalso comprise the actives in nano size form. In other words, the atleast one integrase inhibitor and/or at least one antiretroviral agentor anti-HIV agent can be in the form of nano-size particles. Preferably,these active pharmaceutical ingredients have average particle size lessthan about 2000 nm, preferably less than about 1000 nm.

Nanonization of hydrophobic or poorly water-soluble drugs generallyinvolves the production of drug nanocrystals through either chemicalprecipitation (bottom-up technology) or disintegration (top-downtechnology). Different methods may be utilized to reduce the particlesize of the hydrophobic or poorly water soluble drugs. [Huabing Chen etal., discusses the various methods to develop nano-formulations in“Nanonization strategies for poorly water-soluble drugs,” Drug DiscoveryToday, Volume 00, Number 00, March 2010].

Nano-sizing leads to an increase in the exposure of surface area ofparticles leading to an increase in the rate of dissolution.

The nanoparticles of the present invention may be obtained by any of theprocess such as, but not limited to, milling, precipitation, highpressure homogenization, spray freeze drying, super-critical fluidtechnology, double emulsion or solvent evaporation, Particle replicationin non-wetting templates, thermal condensation, ultrasonication andspray drying.

The nano-milled drugs may be obtained by nano-milling of drugs with atleast one surface stabilizer, at least one viscosity building agent andat least one polymer.

The present invention provides a method of prevention, treatment orprophylaxis of diseases caused by retroviruses, especially acquiredimmune deficiency syndrome or an HIV infection, which method comprisesadministering the pharmaceutical antiretroviral compositionsubstantially as hereinbefore described. There is further provided bythe present invention an antiretroviral composition substantially ashereinbefore described, for use in treating disorders or conditions thatrespond to, or are prevented, ameliorated or eliminated by administeringthe pharmaceutical antiretroviral composition comprising substantiallyas hereinbefore described.

The present invention also provides a pharmaceutical composition assubstantially described herein by reference to the examples.

The following examples are for the purpose of illustration of theinvention only and are not intended in any way to limit the scope of thepresent invention.

Example 1

Manufacturing Formula

Part I : Dolutegravir Layer Sr. No. Ingredients Qty (mg)/Tablet Dry Mix1 Dolutegravir 50.00 2 Microcrystalline Cellulose PH 102 415.00 3Croscarmellose Sodium 25.00 4 Colloidal Silicon Dioxide 2.50 Blending &Lubrication 5 Colloidal Silicon Dioxide 2.50 6 Magnesium Stearate 5.00Total weight Part I 500.00 Part II : Tenofovir & Emtricitabine Layer Sr.No. Ingredients Qty (mg)/Tablet Dry Mix 1 Emtricitabine 200.00 2Tenofovir Disoproxil Fumarate 300.00 3 Microcrystalline Cellulose PH 10250.30 4 Croscarmellose Sodium 31.70 5 Red Oxide Of Iron 0.20 6 MagnesiumStearate 7.70 Blending & Lubrication 7 Croscarmellose Sodium 16.30 8Magnesium Stearate 6.80 Total Weight Part II 613.00 Tablet weight (PartI + Part II) 1113.00 Film Coating to Bilayer Tablet 1 Opadry ™ 27.00 2Purified Water q.s. Final Coated Tablet weight 1140.00

Manufacturing Process:

-   1. All the materials of each part were sifted & dry mixed in    separately.-   2. The sifted material was compacted and sized to get the free    flowing granules of each part.-   3. The granules of each part obtained in step 2 were blended with    croscarmellose sodium and lubricated with pre-sifted with Magnesium    stearate and then compressed into bilayer tablet.-   4. The bilayer tablets were film coated using dispersion of Opadry™.

Example 2

Manufacturing Formula:

Part I : Dolutegravir Layer Sr. Qty (mg)/ No. Ingredients Tablet Dry Mix1 Dolutegravir 50.00 2 Microcrystalline Cellulose PH 102 415.00 3Croscarmellose Sodium 25.00 4 Colloidal Silicon Dioxide 2.50 Blending &Lubrication 5 Colloidal Silicon Dioxide 2.50 6 Magnesium Stearate 5.00Total weight Part I 500.00 Part II : Tenofovir & Lamivudine Layer Sr.No. Ingredients Qty (mg)/Tablet I Tenofovir DF Part 1 TenofovirDisoproxil Fumarate 300.00 2 Croscarmellose Sodium 22.50 3Microcrystalline Cellulose PH 101 45.00 4 Ferric Oxide Yellow 0.20 5Magnesium Stearate 2.50 II Lamivudine Part 6 Lamivudine 300.00 7Croscarmellose Sodium 22.50 8 Microcrystalline Cellulose PH 101 50.60 9Ferric Oxide Yellow 0.20 10 Pregelatinized Starch 18.00 11 MagnesiumStearate 2.50 III Blending & Lubrication 12 Croscarmellose Sodium 30.0013 Magnesium Stearate 6.00 Total Weight of Part II 800.00 Tablet weight(Part I + Part II) 1300.00 Film Coating to Bilayer Tablet 1 Opadry ™32.00 2 Purified Water q.s. Final Coated Tablet weight 1332.00

Manufacturing Process:

-   1. All the materials of each part were sifted & dry mixed    separately.-   2. The sifted material was compacted and sized to get the free    flowing granules of each part.-   3. The granules of each part obtained in step 2 were blended with    croscarmellose sodium and lubricated with pre-sifted with Magnesium    stearate and then compressed into bilayer tablet.-   4. The bilayer tablets were film coated using dispersion of Opadry™.

Example 3

Manufacturing Formula:

Part I : Dolutegravir Layer Sr. No. Ingredients Qty (mg)/Tablet Dry Mix1 Dolutegravir 50.00 2 Microcrystalline Cellulose PH 102 415.00 3Croscarmellose Sodium 25.00 4 Colloidal Silicon Dioxide 2.50 Blending &Lubrication 5 Colloidal Silicon Dioxide 2.50 6 Magnesium Stearate 5.00Total weight Part I 500.00 Part II : Lamivudine & Zidovudine Layer Sr.Qty (mg)/ No. Ingredients Tablet 1 Lamivudine 150.00 2 Zidovudine 300.003 Microcrystalline Cellulose PH 102 269.42 4 Colloidal Silicon Dioxide2.25 5 Sodium Starch Glycolate 22.50 6 Ferric Oxide Yellow 0.20Lubrication 7 Magnesium Stearate 5.63 Total Weight of Part II 750.00Tablet weight (Part I + Part II) 1250.00 Film Coating to Bilayer Tablet1 Opadry ™ 32.00 2 Purified Water q.s. Final Coated Tablet weight1282.00

Manufacturing Process:

-   1. All the materials of each part were sifted & dry mixed    separately.-   2. The sifted material was compacted and sized to get the free    flowing granules of each part.-   3. The granules of each part obtained in step 2 were blended with    croscarmellose sodium and lubricated with pre-sifted with Magnesium    stearate and then compressed into bilayer tablet.-   4. The bilayer tablets were film coated using dispersion of Opadry™.

Example 4

Manufacturing Formula:

Part I : Raltegravir Layer Sr. No. Ingredients Qty/Tablet 1 RaltegravirPotassium 434.40 2 MCC PH102 114.11 3 Lactose Monohydrate 26.06 4Calcium Phosphate Dibasic Anhydrous 73.85 5 Hypromellose 2208 26.06 6Poloxamer 407 (Contains 0.01% BHT) 173.80 7 Sodium Stearyl Fumarate 8.698 Magnesium Stearate 13.03 Total weight Part I 870.00 Part II :Tenofovir & Emtricitabine Layer Sr. No. Ingredients Qty/Tablet Dry Mix 1Emtricitabine 200.00 2 Tenofovir Disoproxil Fumarate 300.00 3Microcrystalline Cellulose PH 102 50.30 4 Croscarmellose Sodium 31.70 5Red Oxide Of Iron 0.20 6 Magnesium Stearate 7.70 Blending & Lubrication7 Croscarmellose Sodium 16.30 8 Magnesium Stearate 6.80 Total WeightPart II 613.00 Tablet weight (Part I + Part II) 1483.00 Film Coating toBilayer Tablet 1 Opadry ™ 37.00 2 Purified Water q.s. Final CoatedTablet weight 1520.00

Manufacturing Process:

-   1. All the materials of each part were sifted & dry mixed    separately.-   2. The sifted material was compacted and sized to get the free    flowing granules of each part.-   3. The granules of each part obtained in step 2 were blended with    croscarmellose sodium and lubricated with pre-sifted with Magnesium    stearate and then compressed into bilayer tablet.-   4. The bilayer tablets were film coated using dispersion of Opadry™.

Example 5

Manufacturing Formula:

Part I : Raltegravir Layer Sr. No. Ingredients Qty/Tablet 1 RaltegravirPotassium 434.40 2 MCC PH102 114.11 3 Lactose Monohydrate 26.06 4Calcium Phosphate Dibasic Anhydrous 73.85 5 Hypromellose 2208 26.06 6Poloxamer 407 (Contains 0.01% BHT) 173.80 7 Sodium Stearyl Fumarate 8.698 Magnesium Stearate 13.03 Total weight of part I 870.00 Part II :Tenofovir & Lamivudine Layer Sr. No. Ingredients Qty/Tablet I TenofovirDF Part 1 Tenofovir Disoproxil Fumarate 300.00 2 Croscarmellose Sodium22.50 3 Microcrystalline Cellulose PH 101 45.00 4 Ferric Oxide Yellow0.20 5 Magnesium Stearate 2.50 II Lamivudine Part 6 Lamivudine 300.00 7Croscarmellose Sodium 22.50 8 Microcrystalline Cellulose PH 101 50.60 9Ferric Oxide Yellow 0.20 10 Pregelatinized Starch 18.00 11 MagnesiumStearate 2.50 III Blending & Lubrication 12 Croscarmellose Sodium 30.0013 Magnesium Stearate 6.00 Total Weight of Part II 800.00 Tablet weight(Part I + Part II) 1670.00 Film Coating to Bilayer Tablet 1 Opadry ™42.00 2 Purified Water q.s. Final Coated Tablet weight 1712.00

Manufacturing Process:

-   1. All the materials of each part were sifted & dry mixed    separately.-   2. The sifted material was compacted and sized to get the free    flowing granules of each part.-   3. The granules of each part obtained in step 2 were blended with    croscarmellose sodium and lubricated with pre-sifted with Magnesium    stearate and then compressed into bilayer tablet.-   4. The bilayer tablets were film coated using dispersion of Opadry™.

Example 6

Manufacturing Formula:

Part I : Raltegravir Layer Sr. No. Ingredients Qty/Tablet 1 RaltegravirPotassium 434.40 2 MCC PH102 114.11 3 Lactose Monohydrate 26.06 4Calcium Phosphate Dibasic Anhydrous 73.85 5 Hypromellose 2208 26.06 6Poloxamer 407 (Contains 0.01% BHT) 173.80 7 Sodium Stearyl Fumarate 8.698 Magnesium Stearate 13.03 Total weight of part I 870.00 Part II :Lamivudine & Zidovudine Layer Sr. No. Ingredients Qty/Tablet 1Lamivudine 150.00 2 Zidovudine 300.00 3 Microcrystalline Cellulose PH102 269.42 4 Colloidal Silicon Dioxide 2.25 5 Sodium Starch Glycolate22.50 6 Ferric Oxide Yellow 0.20 Lubrication 7 Magnesium Stearate 5.63Total Weight of Part II 750.00 Tablet weight (Part I + Part II) 1620.00Film Coating to Bilayer Tablet 1 Opadry ™ 40.00 2 Purified Water q.s.Final Coated Tablet weight 1660.00

Manufacturing Process:

-   1. All the materials of each part were sifted & dry mixed    separately.-   2. The sifted material was compacted and sized to get the free    flowing granules of each part.-   3. The granules of each part obtained in step 2 were pre-sifted with    Magnesium stearate and then compressed into bilayer tablet.-   4. The bilayer tablets were film coated using dispersion of Opadry™.

Example 7

Manufacturing Formula:

Sr. No. Ingredients Qty (mg)/Tablet Dry Mix 1 Dolutegravir 50.00 2Emtricitabine 200.00 3 Tenofovir Disoproxil Fumarate 300.00 4Microcrystalline Cellulose PH 102 350.00 5 Croscarmellose Sodium 25.00Binder 6 Hypromellose E15 cps 20.00 7 Purified Water q.s. Blending &Lubrication 8 Colloidal Silicon Dioxide 2.50 9 MicrocrystallineCellulose PH 102 50.00 10 Croscarmellose Sodium 25.00 11 MagnesiumStearate 7.50 Total weight uncoated tablet 1030.00 Film Coating 12Opadry ™ 25.00 13 Purified Water q.s. Final Coated Tablet weight 1055.00

Manufacturing Process:

-   1. All the materials of each part were sifted & dry mixed    separately.-   2. Binder solution was prepared by adding hypromellose in purified    water-   3. The granules were prepared by spraying binder solution of step 2    on to the dry mix.-   4. The granules obtained were sized and blended with colloidal    silicon dioxide, microcrystalline cellulose and croscarmellose    sodium and further lubricated with magnesium stearate.-   5. The lubricated granules of step 4 were compressed to form tablets    and then film coated with Opadry™ dispersion.

Example 8

Manufacturing Formula:

Sr. No. Ingredients Qty (mg)/Tablet Dry Mix 1 Dolutegravir 50.00 2Tenofovir Disoproxil Fumarate 300.00 3 Lamivudine 300.00 4Microcrystalline Cellulose PH 102 395.50 5 Croscarmellose Sodium 25.00Binder 6 Hypromellose E15 cps 23.00 7 Purified Water q.s. Blending &Lubrication 8 Colloidal Silicon Dioxide 2.50 9 MicrocrystallineCellulose PH 102 50.00 10 Magnesium Stearate 9.00 Total weight Uncoatedtablet 1155.00 Film Coating 11 Opadry ™ 25.00 12 Purified Water q.s.Final Coated Tablet weight 1180.00

Manufacturing Process:

-   1. All the materials of each part were sifted & dry mixed    separately.-   2. Binder solution was prepared by adding hypromellose in purified    water-   3. The granules were prepared by spraying binder solution of step 2    on to the dry mix.-   4. The granules obtained were sized and blended with colloidal    silicon dioxide, microcrystalline cellulose and further lubricated    with magnesium stearate.-   5. The lubricated granules of step 4 were compressed to form tablets    and then film coated with Opadry™ dispersion.

Example 9

Manufacturing Formula:

Sr. No. Ingredients Qty (mg)/Tablet Dry Mix 1 Dolutegravir 50.00 2Lamivudine 150.00 3 Zidovudine 300.00 4 Microcrystalline Cellulose PH102 395.00 5 Croscarmellose Sodium 25.00 Binder 6 Hypromellose E15 cps20.00 7 Purified Water q.s. Blending & Lubrication 8 Colloidal SiliconDioxide 2.50 9 Microcrystalline Cellulose PH 102 50.00 10 MagnesiumStearate 7.50 Total weight uncoated tablet 1000.00 Film Coating 1Opadry ™ 25.00 2 Purified Water q.s. Final Coated Tablet weight 1025.00

Manufacturing Process:

-   1. All the materials of each part were sifted & dry mixed    separately.-   2. Binder solution was prepared by adding hypromellose in purified    water-   3. The granules were prepared by spraying binder solution of step 2    on to the dry mix.-   4. The granules obtained were sized and blended with colloidal    silicon dioxide, microcrystalline cellulose and further lubricated    with magnesium stearate.-   5. The lubricated granules of step 4 were compressed to form tablets    and then film coated with Opadry™ dispersion.

It will be readily apparent to one skilled in the art that varyingsubstitutions and modifications may be made to the invention disclosedherein without departing from the spirit of the invention. Thus, itshould be understood that although the present invention has beenspecifically disclosed by the preferred embodiments and optionalfeatures, modification and variation of the concepts herein disclosedmay be resorted to by those skilled in the art, and such modificationsand variations are considered to be falling within the scope of theinvention.

It is to be understood that the phraseology and terminology used hereinis for the purpose of description and should not be regarded aslimiting. The use of “including,” “comprising,” or “having” andvariations thereof herein is meant to encompass the items listedthereafter and equivalents thereof as well as additional items.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referencesunless the context clearly dictates otherwise. Thus, for example,reference to “a polymer” includes a single polymer as well as two ormore different polymers; reference to a “plasticizer” refers to a singleplasticizer or to combinations of two or more plasticizer, and the like.

What is claimed is:
 1. A pharmaceutical composition that is a singleunit dosage form for oral administration in the form of a coatedbi-layer tablet comprising a first layer and a second layer, wherein thefirst layer comprises from about 1 mg to about 50 mg dolutegravir or itspharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients; and wherein the second layercomprises from about 150 mg to about 300 mg of tenofovir disoproxilfumarate, from about 150 mg to about 300 mg of lamivudine, andpharmaceutically acceptable excipients.
 2. The pharmaceuticalcomposition according to claim 1, wherein tenofovir disoproxil fumarateis present in an amount of 300 mg.
 3. The pharmaceutical compositionaccording to claim 1, wherein lamivudine is present in an amount of 300mg.
 4. The pharmaceutical composition according to claim 1, wherein thecomposition further comprises one or more pharmaceutically acceptableexcipients selected from carriers, diluents, fillers, binders,lubricants, glidants, disintegrants, bulking agents, flavourants or anycombination thereof.
 5. The pharmaceutical composition according toclaim 1, wherein the composition is in the form of a tablet,mini-tablet, granules, sprinkles, capsules, sachets, powders, pellets, aliquid dosage form, injection preparation or in the form of a kit. 6.The pharmaceutical composition according to claim 1, for use in thetreatment of diseases caused by retroviruses.
 7. A process for preparingthe pharmaceutical composition as claimed in claim 1, wherein theprocess comprises the steps of: forming a first layer by admixingdolutegravir with one or more pharmaceutically acceptable excipients;forming a second layer by admixing tenofovir disoproxil fumarate,lamivudine, and pharmaceutically acceptable excipients; and afterforming the first layer and the second layer, combining the first layerand the second layer to form a bi-layer tablet.
 8. The process accordingto claim 7, comprising the steps of: (a) sifting and dry mixing thedolutegravir and pharmaceutically acceptable excipients, and (b) forminggranules of the dolutegravir and optionally pharmaceutically acceptableexcipients.
 9. A process comprising utilizing the pharmaceuticalcomposition according to claim 1, in the manufacture of a medicament forthe treatment of diseases caused by retroviruses.
 10. A method oftreating diseases caused by retroviruses wherein the method comprisesadministering the pharmaceutical composition according to claim 1 to asubject in need thereof.
 11. The method according to claim 10, whereinthe treatment for diseases caused by retroviruses includes the treatmentof acquired immune deficiency syndrome or an HIV infection.